1. Field of the Invention
The invention relates to novel bisacyloxypropylcysteine conjugates and their use, including in the form of pharmaceutical compositions.
2. Description of Related Art
It has been known for a long time that certain lipopeptides are macrophage activators (Hoffman, P., S. Heinle, U. F. Schade, H. Loppnow, A. J. Ulmer, H. D. Flad, G. Jung, and W. Bessler, 1988, “Stimulation of human and murine adherent cells by bacterial lipoprotein and synthetic bisacyoxypropylcysteine analogues”, Immunobiol. 177:158-170). Peptides or proteins which are multiply fatty acid-substituted (acyloxy-substituted) at a propylcysteine residue, and which have a physiological effect, are also known, in particular, within this class of macrophage activators.
However, peptides, and among these lipopeptides having relatively long fatty acid chains, in particular, frequently suffer from what is a serious disadvantage for pharmaceutical and related uses in the human or animal body, i.e that of having too low a solubility in water, with this greatly restricting their activity and their area of use.
These problems can be solved by conjugating the proteins or peptides to water-soluble polymers. For example, EP 0 510 356 B1 discloses polyethylene glycol-protein conjugates in which a protein is bonded to a polyethylene glycol by way of a linker and thereby made considerably more water-soluble. EP 0 510 356 B1 mentions a large number of other documents which describe conjugating peptides or proteins to water-soluble polymers, in this case polyethylene glycol in particular. The conjugation with PEG is nowadays also termed “pegylating”.
Macrophage activators which are pegylated in the above-described manner are already known. For example, a PEG which is acyloxy-substituted three times at a propyl-cysteine residue, i.e. tripalmitoyl-S-glycerylcysteine-polyethylene glycol, which can be designated PAM3-Cys-PEG, can be obtained commercially.
PAM3-Cys-PEG possesses the structure
with the fatty acid-substituted propylcysteine being conjugated to the polyethylene glycol at position X by way of a divalent radical such as —NH—, —OCO—, —S—, —O— or the like.
Despite the very greatly improved water solubility of PAM3-Cys-PEG as compared with the corresponding PAM3-Cys peptides, it is frequently necessary, or at least very advisable, to add an organic solubilizer when using this substance as a macrophage activator since the macrophage activation would otherwise be lower. However, solubilizers such as octylglucoside are not entirely without problems from the pharmacological point of view.
There still remains, therefore, a great need for novel, physiologically well-tolerated, in particular non-immunogenic, macrophage activators which exhibit good solubility in water and are active. The object of the invention is therefore to make available such a novel well-tolerated, water-soluble and highly active macrophage activator.